The present invention relates to a series of new pyridylthiazolinecarboxylic acid amide compounds which we have found to have a valuable combination of antiallergic and antiasthmatic activities with an antagonist activity against Platelet Activating Factor (PAF).
A number of compounds having anti-allergic activities are known, and it is also known that compounds having a heterocyclylalkylamide structure have anti-allergic activity (see, for example, U.S. Pat. No. 4,965,266, Chemical Pharmaceutical Bulletin, 37, p. 1256 (1989), etc.).
PAF (platelet activating factor) exhibits a strong platelet activating and aggregating effect, from which is derives its name. It has, however, in recent years been seen to be a potentially crucial mediator in a wide variety of pathological processes. Thus, it also has a hypotensive effect and increases vasopermeability; it is believed to be an active agent in the induction of the shock state (for example endotoxin-induced shock or anaphylactic shock) and to act as a mediator of inflammatory disease. It has also been found to play an important role in nephritis, myocardial infarction, angina pectoris, asthma, cardiac and systemic anaphylaxis, gastric and intestinal ulceration, psoriasis and immune and renal disorders. In addition, PAF inhibitors also inhibit eosinophile accumulation and could, therefore, be used for the treatment of late allergic reactions.
However, although it has recently appeared to us that it would be desirable to develop anti-allergic agents which not only have anti-allergic activity but also have activities which cooperate with the anti-allergic activity, such as PAF antagonism, no drugs satisfying this demand have yet been put on the market.
For example, while is known that certain thiazolidine derivatives, for example Compound (A) shown below (which is described in U.S. Pat. No. 4,987,132), have PAF antagonism, their anti-allergic activity is very weak. Other prior art compounds described in the same US Patent have anti-PAF activities, but their anti-allergic activity is either also very weak or effectively non-existent. ##STR2##
Japanese Patent Application Kokai No. Hei 2-179 (equivalent to Australian Patent No. 9214013) discloses a number of pyridylthiazolinecarboxylic acid amide compounds which are said to be PAF antagonists, such as the compound of formula (A): ##STR3##
However, the antiallergic activity of these compounds is very weak.
We have now surprisingly found a series of compounds which combine strong anti-allergic, anti-asthmatic and anti-PAF activities, all in the same compound, a combination of activities that, so far as we are aware, has not hitherto been known. Moreover, the compounds of the invention have sufficiently low toxicities to render them of potential value for the treatment and prophylaxis of disorders in, inter alia, human beings.